Project Summary/Abstract Inflammation is central to PH pathogenesis, as a clear trigger of human and experimental disease including autoimmune scleroderma and schistosomiasis infection. Blocking inflammation prevents PH in pre-clinical models, including schistosomiasis and hypoxic sterile inflammation. However, targeting inflammation faces significant challenges, as no therapies have yet been proven to be of clinical benefit. Potential mechanisms that limit this therapeutic approach include: non-targeted immunosuppression suppressing both deleterious and protective pathways; patient-to-patient heterogeneity resulting in only some subsets of patients benefiting, without biomarker identification; and a variable contribution of inflammation to vascular pathology over the disease course. Our research group, working within the context of this PPG submission, is uniquely poised to interrogate mechanisms that link innate and adaptive immunity in PH. We focus on the interplay between complement, monocytes and macrophages in innate immunity, and CD4 T cells in adaptive immunity. Our body of work has demonstrated that Type 2 adaptive immunity driven by Schistosoma exposure (the cause of schistosomiasis, a major PAH etiology), triggers an innate immune response with recruitment of Ly6c+ monocytes, resulting in perivascular thrombospondin-1 (TSP-1) expression, leading to latent TGF-? activation that drives the vascular pathology. We now propose to leverage clearly defined antigenic triggers and mechanistic intermediate and endpoints in Schistosoma-PH to interrogate how complement activates adaptive and innate immunity resulting in vascular remodeling. We will study mechanisms underlying disease persistence versus recovery, focusing on potential dual roles of complement and activated TGF-? as initially inciting of PH, and subsequently suppressing Schistosoma-triggered inflammation and PH as the antigenic burden is cleared. Our third Aim is translational, investigating the peripheral blood immune cell phenotype as it relates to complement and TSP-1 in subjects schistosomiasis, idiopathic and scleroderma-associated pulmonary arterial hypertension, supporting the overall rigor and impact of our studies. Hypothesis: As an innate trigger of adaptive immunity, complement activation is necessary for Type 2 inflammation, monocyte recruitment, and activation of TGF-? by TSP-1, initially contributing to PH and later helping in the resolution of Schistosoma-induced inflammation and PH. Specific Aim 1: To determine that complement is necessary for Type 2 inflammation-driven PH. Specific Aim 2: To determine that complement-dependent TSP-1+ monocyte recruitment contributes to both the initial development and subsequent resolution of Schistosoma-triggered inflammation and PH. Specific Aim 3: To determine that peripheral blood complement levels correlate with leukocyte and cytokine signatures in humans with schistosomiasis, scleroderma and idiopathic PAH. Our overall goal is to identify novel therapeutic targets to safely and effectively target underlying disease drivers in PH, to meaningfully impact the disease course.